Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation

Shabnam Kharazi; Adam J. Mead; Anna Mansour; Anne Hultquist; Charlotta Böiers; Sidinh Luc; Natalija Buza-Vidas; Zhi Ma; Helen Ferry; Debbie Atkinson; Kristian Reckzeh; Kristina Masson; Jörg Cammenga; Lars Rönnstrand; Fumio Arai; Toshio Suda; Claus Nerlov; Ewa Sitnicka; Sten Eirik W Jacobsen

doi:10.1182/blood-2010-06-289207

Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation

Shabnam Kharazi, Adam J. Mead, Anna Mansour, Anne Hultquist, Charlotta Böiers, Sidinh Luc, Natalija Buza-Vidas, Zhi Ma, Helen Ferry, Debbie Atkinson, Kristian Reckzeh, Kristina Masson, Jörg Cammenga, Lars Rönnstrand, Fumio Arai, Toshio Suda, Claus Nerlov, Ewa Sitnicka, Sten Eirik W Jacobsen

Research output: Contribution to journal › Article › peer-review

Abstract

Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3 - internal tandem duplication (Flt3-ITD) - induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin -Sca1 +c-Kit + progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3 ITD/ITD myeloid phenotype is FLT3 ligand-independent. © 2011 by The American Society of Hematology.

Original language	English
Pages (from-to)	3613-3621
Number of pages	8
Journal	Blood
Volume	118
Issue number	13
DOIs	https://doi.org/10.1182/blood-2010-06-289207
Publication status	Published - 29 Sept 2011

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Manchester Cancer Research Centre

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10.1182/blood-2010-06-289207

http://bloodjournal.hematologylibrary.org/content/118/13/3613.full.pdf+html

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Kharazi, S., Mead, A. J., Mansour, A., Hultquist, A., Böiers, C., Luc, S., Buza-Vidas, N., Ma, Z., Ferry, H., Atkinson, D., Reckzeh, K., Masson, K., Cammenga, J., Rönnstrand, L., Arai, F., Suda, T., Nerlov, C., Sitnicka, E., & Jacobsen, S. E. W. (2011). Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. Blood, 118(13), 3613-3621. https://doi.org/10.1182/blood-2010-06-289207

@article{3fa073c5e701400ebe24758269ca3496,

title = "Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation",

abstract = "Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3 - internal tandem duplication (Flt3-ITD) - induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin -Sca1 +c-Kit + progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3 ITD/ITD myeloid phenotype is FLT3 ligand-independent. {\textcopyright} 2011 by The American Society of Hematology.",

author = "Shabnam Kharazi and Mead, {Adam J.} and Anna Mansour and Anne Hultquist and Charlotta B{\"o}iers and Sidinh Luc and Natalija Buza-Vidas and Zhi Ma and Helen Ferry and Debbie Atkinson and Kristian Reckzeh and Kristina Masson and J{\"o}rg Cammenga and Lars R{\"o}nnstrand and Fumio Arai and Toshio Suda and Claus Nerlov and Ewa Sitnicka and Jacobsen, {Sten Eirik W}",

note = "G0501838, Medical Research Council, United KingdomG0801073, Medical Research Council, United KingdomG0900892, Medical Research Council, United Kingdom",

year = "2011",

month = sep,

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doi = "10.1182/blood-2010-06-289207",

language = "English",

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Kharazi, S, Mead, AJ, Mansour, A, Hultquist, A, Böiers, C, Luc, S, Buza-Vidas, N, Ma, Z, Ferry, H, Atkinson, D, Reckzeh, K, Masson, K, Cammenga, J, Rönnstrand, L, Arai, F, Suda, T, Nerlov, C, Sitnicka, E & Jacobsen, SEW 2011, 'Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation', Blood, vol. 118, no. 13, pp. 3613-3621. https://doi.org/10.1182/blood-2010-06-289207

TY - JOUR

T1 - Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation

AU - Kharazi, Shabnam

AU - Mead, Adam J.

AU - Mansour, Anna

AU - Hultquist, Anne

AU - Böiers, Charlotta

AU - Luc, Sidinh

AU - Buza-Vidas, Natalija

AU - Ma, Zhi

AU - Ferry, Helen

AU - Atkinson, Debbie

AU - Reckzeh, Kristian

AU - Masson, Kristina

AU - Cammenga, Jörg

AU - Rönnstrand, Lars

AU - Arai, Fumio

AU - Suda, Toshio

AU - Nerlov, Claus

AU - Sitnicka, Ewa

AU - Jacobsen, Sten Eirik W

N1 - G0501838, Medical Research Council, United KingdomG0801073, Medical Research Council, United KingdomG0900892, Medical Research Council, United Kingdom

PY - 2011/9/29

Y1 - 2011/9/29

N2 - Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3 - internal tandem duplication (Flt3-ITD) - induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin -Sca1 +c-Kit + progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3 ITD/ITD myeloid phenotype is FLT3 ligand-independent. © 2011 by The American Society of Hematology.

AB - Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3 - internal tandem duplication (Flt3-ITD) - induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin -Sca1 +c-Kit + progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3 ITD/ITD myeloid phenotype is FLT3 ligand-independent. © 2011 by The American Society of Hematology.

U2 - 10.1182/blood-2010-06-289207

DO - 10.1182/blood-2010-06-289207

M3 - Article

C2 - 21813452

SN - 0006-4971

VL - 118

SP - 3613

EP - 3621

JO - Blood

JF - Blood

IS - 13

ER -

Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation

Abstract

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